The primary immunologic abnormality resulting from infection by human immunodeficiency virus (HIV) is the progressive depletion and functional impairment of T lymphocytes expressing the CD4 cell surface glycoprotein. The loss of CD4 helper/inducer T cell function probably underlies the profound defects in cellular and humoral immunity leading to the opportunistic infections and malignancies characteristic of the acquired immunodeficiency syndrome (AIDS) (Lane et al., Ann. Rev. Immunol., 3: 477, 1985). Studies of HIV-1 infection of fractionated CD4 and CD8 T-cells from normal donors and AIDS patients have revealed that depletion of CD4 T-cells results from the ability of HIV-1 to selectively infect, replicate in, and ultimately destroy this T lymphocyte subset (Klatzmann et al., Science, 225: 59, 1984).
The widespread use of highly active antiretroviral therapy (HAART) has dramatically improved the clinical course for many individuals infected with HIV (Berrey et al., J. Infect. Dis., 183, (10): 1466, 2001). However, toxicities associated with long term HAART have put a high priority on the design and development of less toxic therapies. Another antiviral inhibitor is T-20 (Wild et al., Proc. Natl. Acad. Sci. U.S.A, 91, No. 26: 12676, 1994; Wild et al., Proc. Natl. Acad. Sci. U.S.A. 89, No. 21: 10537, 1992), a relatively non-toxic peptide that disrupts viral fusion thereby protecting CD4+ lymphocytes from de novo infection. In clinical trials, T-20 has been shown to reduce plasma viral load by up to two logs (Kilby et al., Nat. Med., 4, No. 11: 1302, 1998).
The strategy underlying these CD4 based therapies, i.e. blocking the interaction between gp120 and the CD4 receptor, encompasses advantages distinct from current HAART regimens. The CD4 binding site on gp120 includes highly conserved residues; thus, agents targeting this site are unlikely to encounter resistance mutants. Additionally, such agents, by blocking de novo infection, may prevent the expansion of viral reservoirs.
Monomeric soluble CD4 (sCD4) was one of the first reagents in this group to be tested clinically (Schooley et al., Ann. Intern. Med., 112, No. 4: 247, 1990). Unfortunately, sCD4 failed to demonstrate significant antiviral activity in vivo (Id.). Among the problems inherent to sCD4 was its inability to efficiently neutralize primary isolates of HIV. Thus, sCD4 is not the therapeutic agent of choice for treating HIV. Thus, a need remains for additional agents that can be used to study HIV infection in vitro, and is of use for treating or preventing HIV replication in vivo.